Regulation of the B-Cell Development and Differentiation

免疫应答的多样性和特异性由细胞表面的抗原结合受体体现。 B和T淋巴细胞。增殖性扩张和程序性消除之间的平衡 活化或自身反应性细胞也受到这些抗原受体的严格调节。免疫球蛋白D（IgD） IgM和IgM是两种主要的抗原受体同种型，它们表达在绝大多数的外周B细胞上， 人类和老鼠虽然许多证据表明IgM在驱动B细胞发育中很重要，但IgM在B细胞发育中起着重要作用。 IgD的作用尚不清楚，IgM和IgD在调节体液免疫中的作用也不清楚。 应答最近，我们证明IgM和IgD在淋巴内稳态和免疫调节中具有不同的作用。 胸腺依赖性体液免疫反应。这些新的发现支持了一个模型，其中信号 通过8或p.重链的事件差异调节B细胞发育和分化。这个项目 将解决几个关键问题的机制如何IgM和IgD受体差异 在B细胞发育过程中，使用IgM缺陷型和IgD缺陷型调节细胞存活/生长和细胞死亡。 缺陷小鼠模型。实验还将研究当IgM或IgD被免疫时的免疫应答。 无托叶进一步的研究将探讨VDJ重排和B细胞的功能，表达多种 IgM +/-杂合子中的重链。拟议的研究将阐明IgM的独特功能特征， 和IgD抗原受体，并阐明了B细胞稳态和B细胞免疫的机制，这可能 导致更好地理解免疫缺陷和自身免疫的分子和细胞基础 紊乱

The diversity and specificity of an immune response is embodied by the antigen-binding receptors on both B and T lymphocytes. The balance between proliferative expansion and programmed elimination of activated or autoreactive cells is also tightly regulated by these antigen receptors. Immunoglobulin D (IgD) and IgM are the two major antigen receptor isotypes expressed on the vast majority of peripheral B cells in humans and mice. While much evidence indicates that IgM is important in driving B-cell development, the contribution of IgD remains unclear, as are the roles of IgM and IgD in regulating humoral immune responses. Recently, we demonstrated that IgM and IgD have distinct roles in lymphoid homeostasis and in thymus-dependent humoral immune responses. These novel findings support a model in which signaling events through 8 or p. heavy chain differentially regulate B cell development and differentiation. This project will address several critical questions about the mechanisms how IgM and IgD receptors differentially condition cell survival/growth and cell death during B cell development using both IgM-deficient and IgD- deficient mouse models. Experiments will also investigate immune responses when either IgM or IgD is absent. Additional studies will probe the VDJ rearrangements and functions of B cells expressing multiple heavy chains in IgM +/- heterozygotes. The proposed studies will elucidate distinct functional features of IgM and IgD antigen receptors and illuminate mechanisms of B-cell homeostasis and B-cell immunity, which may lead to better understanding the molecular and cellular basis of immunodeficiency and autoimmune disorders.